Hereditary long QT syndrome (LQTS) is a genetic disorder caused by mutations in one or more ion channel subunits expressed in the heart. LQTS is characterized by delayed or prolonged cardiac repolarization in electrocardiogram with increased risks of developing polymorphic ventricular tachycardia (torsade de pointes, TdP), syncope and sudden cardiac death. To date, LQTS has been associated with over 500 different mutations in at least 13 genes encoding cardiac ion channel proteins. Genotype to phenotype penetrance is estimated to be 60-70% depending on location of the mutation, with more severe phenotypes arising from mutations around the pore-forming regions Matsa E, et al., Eur Heart J 2011; 32: 952-962).
LQTS2 implicates hERG (human ether-a-go-go related gene), a gene (KCNH2) that codes for a protein known as Kv11.1, which constitutes the pore-forming α subunit of the rapidly-activating delayed rectifier potassium current (IKr). Heterozygote KCNH2 mutations exert a dominant-negative effect on wild-type hERG channel associated IKr currents (Thomas D, et al., Cardiovascular research 2003; 60:235-241; Shieh C C, et al., Pharmacological reviews 2000; 52:557-594) by impaired trafficking pathways or altered channel kinetics of the resulting co-assembled hERG heterotetramers. Current non-cardiac heterologous expression systems in HEK 293 or CHO cells have implicated endoplasmic reticulum (ER) sequestering of hERG (Thomas D, et al., Cardiovascular research 2003; 60:235-241; Ficker E, et al., Journal of molecular and cellular cardiology 2000; 32:2327-2337) as a probable cause of LQTS2 manifestation (Thomas D, et al., Cardiovascular research 2003; 60:235-241). However, inability to accurately model the disease in heterologous systems (Itzhaki I, et al., Nature 2011; 471:225-229) and the lack of in vitro humanized diseased cardiomyocytes (CMs) have significantly hindered a true mechanistic understanding of this disease.
Disease-specific induced pluripotent stem cells offer a unique opportunity for disease modeling. Such models yield previously unavailable insights into the molecular basis of disease manifestations that could serve as an invaluable platform for risk stratification and drug discovery. In this study, we show that CMs derived from LQTS2 patient-specific (A561V mutant) hiPSC recapitulate the disease phenotype with defective trafficking of hERG channel in vitro and demonstrate phenotypic reversal through pharmacological intervention of ER-Golgi export machinery.
This is the first time being shown that such allelic dominance is only manifesting itself in cardiomyocytes and not in other unrelated cells in the same patient. Therefore, this pathology and potential treatment of LQTS2 can only be studied and demonstrated in cardiomyocytes where the disease originated in the first place, but not in other cellular systems from the same patient such as the original patient skin fibroblasts or their undifferentiated iPSC-derived from the said fibroblasts.